Is PHGDH p.Ala124Val (c.371C>T) pathogenic?

PHGDH p.Ala124Val (c.371C>T) is classified Uncertain significance in PHGDH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.9036); Ultra-rare (popmax 0.0111%, eas); Associated with Inborn genetic diseases.

What condition is associated with PHGDH p.Ala124Val (c.371C>T)?

PHGDH p.Ala124Val (c.371C>T) is associated with Inborn genetic diseases, PHGDH deficiency (ClinVar).

How common is PHGDH p.Ala124Val (c.371C>T) in the general population?

PHGDH p.Ala124Val (c.371C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about PHGDH p.Ala124Val (c.371C>T)?

AlphaMissense predicts likely pathogenic (score 0.9036) — an in-silico prediction, not a clinical call.

PHGDH p.Ala124Val

c.371C>T · rs749596483 · VCV2197572

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9036 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9036	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -11.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 32 kb · p 0.037 · regional, not allelic
Overall
CADD	33.0	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 0.0111% East Asian · 5/44,898 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.0018% 29/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,980
South Asian	0.00549%	18,216
African / African-American	0.00267%	37,457
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.00136%	73,747

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.Ala124Val
Coding: c.371C>T
MANE Select: NM_006623
dbSNP: rs749596483
Type: single nucleotide variant
Location: chr1:119726865 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB
Residue 124: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: PHGDH deficiency

Similar variants

PHGDH p.Ala124= Likely benign ★ same residue
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

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-ala124val (accessed [today's date]).

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