Is PHGDH p.Ala366Ser (c.1096G>T) pathogenic?

PHGDH p.Ala366Ser (c.1096G>T) is classified Conflicting classifications of pathogenicity in PHGDH (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-13). AlphaMissense: likely benign (0.1102); Ultra-rare (popmax 0.0383%, amr); Associated with PHGDH deficiency.

What condition is associated with PHGDH p.Ala366Ser (c.1096G>T)?

PHGDH p.Ala366Ser (c.1096G>T) is associated with PHGDH deficiency, Neu-Laxova syndrome 1 (ClinVar).

How common is PHGDH p.Ala366Ser (c.1096G>T) in the general population?

PHGDH p.Ala366Ser (c.1096G>T) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about PHGDH p.Ala366Ser (c.1096G>T)?

AlphaMissense predicts likely benign (score 0.1102) — an in-silico prediction, not a clinical call.

PHGDH p.Ala366Ser

c.1096G>T · rs138515760 · VCV647932

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHGDH deficiency

Computational evidence

Protein change
AlphaMissense	0.1102	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -6.76	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 2.1	GERP -0.52, phastCons 0.98
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.037 · regional, not allelic
Overall
CADD	13.18	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0383% Admixed American · 23/59,998 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00397% 64/1,613,310 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,609
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.00961%	10,408
European (non-Finnish)	0.0028%	35,739
African / African-American	0.00134%	74,892

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: PHGDH
Protein: p.Ala366Ser
Coding: c.1096G>T
MANE Select: NM_006623
dbSNP: rs138515760
Type: single nucleotide variant
Location: chr1:119741784 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB

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

Disease context

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

Also linked: Neu-Laxova syndrome 1

Similar variants

PHGDH c.1078+1G>A Likely pathogenic ★★ same condition
PHGDH c.138+1G>T Likely pathogenic ★★ same condition
PHGDH c.139-2A>G Likely pathogenic ★★ same condition
PHGDH c.290+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.357-1G>A Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.412-1G>C Likely pathogenic ★★ same condition
PHGDH c.643+1G>A Likely pathogenic ★★ same condition
PHGDH p.Arg135Trp Pathogenic/Likely pathogenic ★★ 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/phgdh-p-ala366ser (accessed [today's date]).

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