Is LCT p.Arg1908His (c.5723G>A) pathogenic?

LCT p.Arg1908His (c.5723G>A) is classified Uncertain significance in LCT (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-24). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.0535%, eas); Associated with congenital lactase deficiency.

What condition is associated with LCT p.Arg1908His (c.5723G>A)?

LCT p.Arg1908His (c.5723G>A) is associated with congenital lactase deficiency (ClinVar).

How common is LCT p.Arg1908His (c.5723G>A) in the general population?

LCT p.Arg1908His (c.5723G>A) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

How is Congenital lactase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LCT p.Arg1908His (c.5723G>A)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

LCT p.Arg1908His

c.5723G>A · rs577825311 · VCV1032814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital lactase deficiency

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.3	GERP -4.8
Regional constraint	o/e 0.69	unconstrained · MANE · 19 kb · p 6.6e-18 · regional, not allelic
Overall
CADD	0.043	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0535% East Asian · 24/44,892 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00322% 52/1,613,988 alleles · ultra-rare exomes 49/1,461,822 · genomes 3/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0535%	1,871
Admixed American	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00186%	53,638
African / African-American	0.00134%	74,894

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: LCT
Protein: p.Arg1908His
Coding: c.5723G>A
MANE Select: NM_002299
dbSNP: rs577825311
Type: single nucleotide variant
Location: chr2:135788385 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.63
Residue 1908: the 'required for homodimerization and transport to the plasma membrane' region

Full LCT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital lactase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital lactase deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

LCT p.Arg1908Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
LCT p.Arg1908Ser Uncertain significance ★ ⚠ same residue
LCT p.Arg1908= Likely benign ★ same residue
LCT c.4866+2T>G Likely pathogenic ★★ same condition
LCT p.Gln1179Ter Pathogenic/Likely pathogenic ★★ same condition
LCT p.Tyr1390Ter Pathogenic ★★ same condition
LCT c.4173+5G>A Uncertain significance ★★ same condition
LCT p.Ala94Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/lct-p-arg1908his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown