Is GHITM p.Phe256Ser (c.767T>C) pathogenic?

GHITM p.Phe256Ser (c.767T>C) is classified Uncertain significance in GHITM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.7455); Very rare (popmax 0.00221%, sas).

How common is GHITM p.Phe256Ser (c.767T>C) in the general population?

GHITM p.Phe256Ser (c.767T>C) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about GHITM p.Phe256Ser (c.767T>C)?

AlphaMissense predicts likely pathogenic (score 0.7455) — an in-silico prediction, not a clinical call.

GHITM p.Phe256Ser

c.767T>C · VCV4836926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7455	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -10.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 11 kb · p 0.64 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00221% South Asian · 2/90,462 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000187% 3/1,606,726 alleles · very rare exomes 2/1,454,376 · genomes 1/152,350 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,231
European (non-Finnish)	8.5e-05%	1,176,068

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: GHITM
Protein: p.Phe256Ser
Coding: c.767T>C
MANE Select: NM_014394
Type: single nucleotide variant
Location: chr10:84150229 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 77.05

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

Similar variants

GHITM p.Met129Val Uncertain significance ★★ ⚠ same type
GHITM p.Ala109Gly Uncertain significance ★ same type
GHITM p.Ala113Ser Uncertain significance ★ ⚠ same type
GHITM p.Ala144Thr Uncertain significance ★ ⚠ same type
GHITM p.Ala279Ser Uncertain significance ★ ⚠ same type
GHITM p.Ala279Val Uncertain significance ★ ⚠ same type
GHITM p.Ala302Glu Uncertain significance ★ ⚠ same type
GHITM p.Arg10Trp Uncertain significance ★ ⚠ same type

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/ghitm-p-phe256ser (accessed [today's date]).

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